The present invention relates to the use of 7-hydroxylated steroids for the preparation of cosmetic or dermatological compositions for preventing and/or treating the cutaneous effects of aging and of the action of ultraviolet irradiation.
The formation of steroid hormones, their interrelations and their functions have been widely described in the prior art. The functions of pregnenolone (PREG) and of dehydroepiandrosterone (DHEA) as well as of certain of their derivatives are especially mentioned in the PCT patent application published under the number WO 94/08588.
DHEA and its sulfate derivative (S-DHEA) circulate in a significant quantity in adult men, but its level decreases with age (Orentreich et al., J. Clin. Endocr. Metab. 59: 551-555, 1984). It was thus proposed, for example in the French patent application published under the number 2 729 854 or the corresponding European patent application published under the number 723 775, to use S-DHEA in a cosmetic composition for topical application which is intended for the treatment of certain signs of aging. Multiple effects of DHEA have been described, but some of them oppose the processes and the pathologies associated with aging (Watson et al., Drug and Aging 9: 274-291, 1996).
Despite numerous experiments, it has not been possible to prove any of the explanations advanced for the effects of DHEA (Kalimi et al., Molec. Cell. Biochem. 131: 99-104, 1994), and the therapeutic use of DHEA has revealed undesirable secondary effects, in particular in women, as a potential precursor of androgenic hormones.
It has now been shown that the 7-hydroxylated derivatives of PREG and of DHEA are formed by an enzymatic system present in numerous tissues and organs, including the skin, where they favor the mechanisms connected with immunity (Morfin and Courchay, J. Steroid Biochem. Molec. Biol. 50: 91-100, 1994). Like the levels of circulating DHEA, the activity of these hydroxylating enzymes decreases with age (Doostzadeh and Morfin, Steroids 61: 613-620, 1996).
The Applicant is therefore interested in the effects of 7-hydroxylated steroids and their derivatives on cells which form the human skin and which are affected during aging or after UV irradiation. The research work carried out by the Applicant has allowed it to be demonstrated that the effects of glucocorticoids leading to cell apoptosis are cancelled out by the 7-hydroxylated steroids and that their action on the cutaneous cells is manifested by beneficial and protective effects.
Surprisingly, the results obtained with the compounds of the invention do not correspond to those conventionally expected with steroid hormones. Indeed, the hydroxylation process carried out by the body on PREG or DHEA is irreversible, and therefore the conventional steroid hormones cannot be produced from 7-hydroxylated derivatives.
Consequently, the use of 7-hydroxysteroids for cosmetological purposes for treating or preventing the cutaneous effects of aging has outstanding advantages with respect to the steroids of the cosmetic compositions of the prior art.
The recent work concerning the cutaneous modifications caused by age or UV and their medical treatment specifically envisages retinoic acid, xcex1-hydroxy acids and DHEA, but does not mention 7-hydroxysteroids (Gilchrest, Brit. J. Dermatol. 135: 867-875, 1996; Watson et al., Drugs and Aging 9: 274-291, 1996).
The production of 7-hydroxylated derivatives of DHEA has been known for a long time in the tissues of the human fetus (Sulcova et al., Endocr. Experiment. 2: 167-172, 1968), and in the amniotic epithelium (Sulcova et al., J. Steroid Biochem. 7: 101-104, 1976), the human liver (Starka, Sond. Zeit. Natur. 17: 1-2, 1965), human testicles and epididymis (Sulcova and Starka, Experimentia 28: 1361-1362, 1972) and in human preadipocytes (Khalil et al. J. Steroid Biochem. Molec. Biol. 46: 585-594, 1993). In addition, the circulating levels of 7xcex1-hydroxy-DHEA have been measured in premenopausal women at 200-300 pg/ml (Skinner et al. Steroids 30: 315-330, 1977), and 3xcex2,7xcex1-dihydroxy-5xcex1-androstan-17-one (7xcex1-dihydroxyisoandrosterone) has been characterized in human urine (Jacolot et al. J. Steroid Biochem. 14: 663-669, 1981). More recently, the phenomenon of 7-hydroxylation has been extended to other steroids which have, in common with DHEA, a 3xcex2-hydroxylated structure. These are PREG (Akwa et al. Biochem J. 288: 959-964, 1992; Morfin and Courchay J. Steroid Biochem. Molec. Biol. 50: 91-100, 1994), 5xcex1-androstane-3xcex2, 17xcex2-diol (Morfin et al. Biochimie. 59: 637-644, 1977; Morfin et al. J. Steroid Biochem. 12: 629-632, 1980), 3xcex2-hydroxy-5xcex1-androstan-17-one (Akwa et al. Biochem. J. 288: 959-964, 1992) and 3xcex2-hydroxy-5xcex1-pregnan-20-one (Stromstedt et al. Molec. Pharmacol. 44: 1077-1083, 1993).
Some work on 7-hydroxylated steroids proved that they were without characteristic hormonal effects of both androgenic and estrogenic type or on the secretion of pituitary hormones (Celotti et al. J. Steroid Biochem. 18: 397-401, 1983; Sunde et al. J. Steroid Biochem. 16: 483-488, 1982). All of these results therefore lead to the 7-hydroxylation of steroids being considered as a terminal process of hormonal inactivation leading to the urinary and biliary excretion of the 7-hydroxylated steroids produced (Ofner et al. J. Steroid Biochem. 11: 1367-1379, 1979; Strxc3x6mstedt et al. Molec. Pharmacol. 44: 1077-1083, 1993; Khalil et al. J. Steroid Biochem. Molec. Biol. 48: 545-552, 1994). It is only very recently that it has been possible in part to explain the multiple effects noted with DHEA (Watson et al. Drug and Aging 9: 274-291, 1996) by the immunostimulatory properties of its 7-hydroxylated derivatives (Morfin and Courchay J. Steroid Biochem. Molec. Biol. 50: 91-100, 1994; Padgett and Loria J. Immunol. 153: 1544-1552, 1994; Loria et al. J. Endocrinol. 150: S209-S220, 1996). The antiglucocorticoid properties shown by 7xcex1- and 7xcex2-hydroxy-DHEA have been proved and extended to other 7-hydroxylated steroids like those described in the PCT patent applications published under the numbers WO 93/20687 and WO 94/08588 for their role in the triggering of immune processes.
It therefore appears that DHEA and the production of its 7-hydroxylated derivatives decrease with age although that of the glucocorticoids does not vary. In the course of aging, the contribution of hormonal steroids to the cutaneous level is therefore found to be modified with a predominance of glucocorticoids whose promoter effects on cutaneous aging are known.
Consequently, a localized contribution of 7-hydroxylated steroids endowed with a particular but natural antiglucocorticoid effect allows the treated skin to be restored to its youthful steroid context.
However, these properties have never been described or suggested in the prior art. Thus, the PCT patent application published under the number WO 94/08588 does not describe or teach any cosmetic or dermatological application of steroid hormone derivatives. In addition, this patent application is directed at steroidal derivatives in which the substitutions in positions 3 and 7 indicated in the formula (I) below are either hydroxyls or ester functions of 1 to 10 carbon atoms.
The European patent application published under the number 415 766 describes the use of retinoid agents for combating cutaneous atrophy by an antiglucocorticoid mechanism. However, no structural relationship exists between the retinoids (vitamin A and its derivatives) and the steroids.
The European patent application published under the number 189 738 describes the use of dehydroepiandrosterone (DHEA) and of its ester derivatives for treating drying out of the skin, but these compounds are different from the steroids which are the subject of the present invention.
The European patent application published under the number 723 775 envisages the use of the sulfate of DHEA in cosmetic and dermatological compositions and suggests the addition to these compositions of steroid hormones other than the sulfate of DHEA, such as androgens, estrogens and progestagens. However, as indicated above, these steroids are without hormonal action, and their use only has the aim of alleviating the undesirable hormonal effects of DHEA and of the sulfate of DHEA. In addition, the sulfate of DHEA has no structural relationship with the steroids which are the subject of the present invention.
The invention therefore relates to the use, in a cosmetic or dermatological composition for topical application intended to prevent or treat the symptoms of cutaneous aging and/or the effects of UV irradiation on the skin, of a 7xcex1- or 7xcex2-substituted compound of DHEA or of PREG, which is or is not reduced in position 5, and thus corresponding to the formula: 
in which:
R1 is selected from: a hydrogen atom, organic acid ester of 1 to 24 carbon atoms, sulfuric ester or phosphoric ester functions, or carbon-containing ether of 1 to 24 carbon atoms comprising zero or a number of nitrogen atoms, carbohydrate ethers of 3 to 100 carbon atoms and their derivatives including those comprising or not comprising one or a number of nitrogen atoms.
R2 is selected from: a hydrogen atom or a fatty acid ester function of 1 to 24 carbon atoms.
R3 is selected from: a hydrogen atom, an xe2x80x94OH group, the groups of formulae: xe2x80x94COxe2x80x94R4, xe2x80x94CHOHxe2x80x94R4, xe2x95x90CHxe2x80x94CH3, xe2x95x90COHxe2x80x94CH3, xe2x80x94CHR4xe2x80x94CH3, xe2x95x90O, in which R4 is an alkyl group comprising 1 to 10 carbon atoms, preferably methyl, which is substituted or unsubstituted.
The compounds of the invention are 7xcex1- or 7xcex2-substituted derivatives of DHEA or PREG and more particularly still 7xcex1- or 7xcex2-hydroxylated derivatives which are or are not reduced in position 5.
A preferred group of compounds of the invention are the 7xcex1-hydroxylated derivatives, that is to say those in which the oxygen carried in position 7 is axial (7xcex1) and the substituent R2 is a hydrogen.
Another group of preferred compounds of the invention are those where R1 is hydrogen, especially 7xcex1-hydroxy-DHEA and 7xcex1-hydroxyisoandrosterone where R3 is a ketone (xe2x95x90O).
It is expedient to observe that the derivatives of the invention in which R1 is an organic acid have an increased fat solubility which offers the advantage of improving the retention of these compounds in the cells, especially at the level of membranes, and consequently of prolonging their activity and their effect on the cutaneous cells. Among these derivatives, those are preferred in which R1 is a palmitate, an oleate or a ferulate, and especially 3xcex2-palmitoyl-7"xgr"-hydroxy-DHEA, 3xcex2-oleyl-7"xgr"-hydroxy-DHEA and 3xcex2-feruloyl-7"xgr"-hydroxy-DHEA.
The cosmetic or dermatological compositions of the invention can comprise or one or more steroid derivatives according to the invention, as well as other compounds known for their cosmetological or dermatological property, like hormones and, of course, the adjuvants or vehicles conventionally used in these fields.
For the use of a steroid derivative of the invention in a cosmetic composition intended to compensate, treat and/or prevent the cutaneous effects of aging and/or the effects of UV irradiation on the skin, said derivative is administered at a dose of between 0.05 and 10 mg per application and per day and preferably between 0.05 and 5 mg per application and per day.
The effect of restoration or of prevention of cutaneous aging in people of a certain age as well as protective effects with respect to UV is applicable for any treatment aiming to restore the cutaneous tone, tone up the skin and smooth out wrinkles.
On account of their nature, the derivatives of the invention can be employed in very diverse pharmaceutical forms for their percutaneous administration. These can be forms resulting from the addition to the derivatives of the invention of cosmetically acceptable compounds and allowing creams, pastes, gels, lotions, xe2x80x9cwater-in-oilxe2x80x9d or xe2x80x9coil-in-waterxe2x80x9d emulsions as well as forms composed of liposomes of simple or mixed micelles or other penetration promoters such as lysophospholipids, cyclodextrins, polyethylene glycol, surfactants, alcohols, fatty acids and vegetable oils to be produced. This list is not limiting and any other presentation known to man can be envisaged since it is adapted to the steroid derivatives of the invention which have, as a characteristic, the property of being water-soluble and fat-soluble at the same time. Thus, the cosmetic or dermatological compositions of the invention can be present in the form of creams, lotions, gels and ointments or any other form generally used for topical applications.
Other advantages and characteristics of the invention will appear on reading the examples which follow, given in a non-limiting capacity, and showing the performances obtained by the derivatives of the invention as antiapoptotic and anti-free radical agents and promoters of the proliferation of human cutaneous cells.